In the case of diseases of multifactorial origin such as cardiovascular, cerebrovascular, neurodegenerative, neuropsychiatric and neurological, a single medication is not enough to treat them effectively, so a multiple medication therapy should be used. There are two main reasons for the absence of drugs for the treatment of these diseases: 1) drugs targeting a single pathological mechanism and 2) use of high doses that increases the risk of adverse reactions.
Neurodegeneration is a common theme of many diseases of the nervous system and disorders such as dementia, Alzheimer's disease (AD), Parkinson's disease (PD). These diseases are devastating and expensive to manage, while current treatments are inadequate. The urgency of this problem is compounded by the fact that the incidence of these age-related diseases is increasing rapidly due to the demographic changes that are occurring.
The progressive aging of the world population brings with it the unwanted consequence of an increase in neurodegenerative diseases and senile dementias.
PD is a neurodegenerative disease, with symptoms of motor dysfunction: slow movements, rigidity, resting tremor and alterations in balance. As the disease progresses, many patients develop non-motor symptoms, including anxiety, depression, constipation, and dementia.
These characteristics are attributed to a large reduction in the striatal content of dopamine and to a loss of dopaminergic neurons in the substantia nigra pars compacta (Gauthier, 1982).
Clinical signs of PD appear after dopaminergic neuronal death exceeds a threshold of 70-80% and a loss of striatal nerve endings exceeding 50-60% (Agid, 1991).
Investigations of the developmental mechanisms of PD have indicated that the loss of dopaminergic neurons in the nigra pars substance compact is related to the mitochondrial-I complex deficit (Jenner 1998).
Although there are drugs that relieve Parkinson's symptoms, the chronic use of these drugs is not effective in preventing the progression of PD and has been associated with debilitating side effects. It is therefore of great interest to develop neuroprotective therapies that delay or even stop the degenerative progression.
Worldwide, an estimated 46.8 million people live with dementia. This number is estimated to increase almost twice every 20 years; to 74.7 million in 2030 and 131.5 million by 2050. Dementia also has a huge economic impact. Today, the estimated total worldwide cost of dementia is $818 trillion, and it will be a trillion dollar disease by 2018; with a huge impact on the quality of life of patients and their families and caregivers (Alzheimer's Disease International, World Alzheimer Report 2015. London: Alzheimer's Disease International, 2015)
Of all of them, AD is the most prevalent with about 35 million people suffering from the disease and it is estimated that its incidence will increase significantly in the next three decades, along with the increase in the average age of the population (Reitz, C. Brayne, C. Mayeux, R. Epidemiology of Alzheimer's disease, Nat. Rev. Neurol., 2011, 7, 137-152) (Reitz, C., Mayeux, R. Alzheimer disease: Epidemiology, diagnostic criteria, Risk factors and biomarkers, Biochem, Pharmacol., 2014, 88, 640-651).
AD, is a neurodegenerative disorder of the brain that leads to slow progression of memory and cognitive functions; often accompanied by behavioral alterations such as aggression and depression (Querfurth, H. W., LaFerla, F. M. Alzheimer's disease, N. Engl. J. Med., 2010, 362, 329-344). In its last stage it leaves the patient in bed, incontinent and dependent on care and custody, which is very expensive for the relatives. Death occurs, on average, 9 years after diagnosis (Citron M. (2004), Strategies for disease modification in Alzheimer's disease, Nat Rev Neurosci 5 (9): 677-85). The large number of people suffering from this disease and requiring constant care and other services will severely affect medical, monetary, and human resources (Suh Y H and Checler F. (2002).) Amyloid precursor protein, presenilins, and alpha-15 synuclein: molecular pathogenesis And pharmacological applications in Alzheimer's disease, Pharmacol Rev. 54 (3): 469-525). Amyloid precursor protein, presenilins, and alpha-15 synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev. 54 (3): 469-525) Thus, it is a growing medical concern.
Cerebral ischemia is one of the leading causes of death and the first one of disability in adults in many countries (Mukherjee, D., Patil, C G, 2011. Epidemiology and the global burden of stroke, World Neurosurg. 76, S85-S90) Currently only tissue plasminogen activator is the drug that is approved for use in human therapy during the acute phase of cerebral ischemia (Howells, D W, Donnan, G A, 2010.) Comes from? PLoS Med. 7, e1000224). Despite the preclinical hopeful results obtained, none of the candidates evaluated has shown consistent clinical improvements. This may be due to the multiplicity of mechanisms involved in the cascade of neuronal damage after cerebral ischemia, which contrasts with the more simplistic view of the proposed neuroprotectors (Minnerup, J., Schäbitz, W R., 2009. Multifunctional actions of approved and Candidate stroke drugs, Neurotherapeutics 6, 43-52). Accumulated preclinical evidence indicates that a highly selective ligand for a given biological target does not always result in a clinically effective drug, particularly in those pathologies involving multiple factors, such as cerebral ischemia. Therefore, drugs acting at a single site in the ischemic cascade, such as Ca2+ blockers, glutamate antagonists, GABA agonists, antioxidants/free radical scavengers, phospholipid precursors, and anti-inflammatory agents Have generally failed to be clinically effective (Ginsberg, M D, 2008. Neuroprotection for ischemic stroke: past, present and future, Neuropharmacology 55, 363-389).
Emergent neuroprotective approaches have begun to consider mitochondrial bioenergetic dysfunction. There is evidence to suggest that mitochondria play a key role in ischemic neuronal damage by the activation of noxious signals either by structural and functional damage or by amplification of the cascade, which eventually leads to cell death (Christophe, M., Nicolas, S., 2006. Mitochondria: a target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr. Pharm. Des. 12, 739-757) (Mazzeo, A T, Beat, A., Singh, A., Bullock, M R, 2009. The role of mitochondrial transition pore and its modulation intraumatic brain injury and delayed neurodegeneration after TBI. Exp. Neurol. 218, 363-370) (Perez-Pinzon, M A, Stetler, R A, Fiskum, G., Mitochondrial targets for neuroprotection, J. Cereb. BloodFlow. Metab, 32, 1362-1376). Therefore, there is a growing interest in the identification of new classes of compounds that act simultaneously on certain toxic processes in ischemic neurons, including those acting at the mitochondrial level.
Phenolic or polyphenolic derivatives have been widely reported in the literature to be used in the treatment of diseases of the central nervous system, however, their high water solubility (mainly given by hydroxyl groups), make these compounds have difficulty crossing the blood brain barrier and access the brain. The inventors have obtained the product (5-[(3,4-dihydroxyphenyl) methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione) or KM 34:

Meldrum (2,2-dimethyl-1,3-dioxane-4,6-dione) acid and its derivatives have been used intensively as starting materials for the synthesis of many heterocycles, in particular to evaluate their potential biological activity.

The condensation of Meldrum acid with aromatic aldehydes has been developed in an ethanol-water solution with the presence of catalyst by a highly efficient photochemical process with the environment (A novel light induced Knoevenagel condensation of Meldrum's acid with aromatic aldehydes in aqueous ethanol. Somnath Ghosh, Jhantu Das, Subhagata Chattopadhyay, Tetrahedron Letters, Volume 52, Issue 22, 1 Jun. 2011, Pages 2869-2872).

These derivatives show antimicrobial activity. Another series of arylidene analogs of Meldrum's acid (Sandhu H S and all (2010) Synthesis and biological evaluation of arylidene analogues of Meldrum's acid as a new class of antimalarial and antioxidant agents Bioorg Med Chem. 2010 Aug. 1; 18 (15): 5626-33) were evaluated in vitro showing antimalarial and antioxidant activities, as well as inhibitors of platelet aggregation (Abdelaziz El Maatougui, JhonnyAzuaje, Alberto Coelho, Ernesto Cano, Matilde Yanez, Carmen Lopez, Vicente Yaziji, Carlos Carbajales and Eddy Sotelo (4)) Discovery and Preliminary SAR of 5-Arylidene-2,2-Dimethyl-1,3-Dioxane-4,6-Diones as Platelet Aggregation Inhibitors Pages 551-554 (4))
Several patents protect this type of compounds, as well as their use with therapeutic properties. The patent ES2074770 shows the procedure for the preparation of 1,3-dioxane-4,6-dione derivatives.

Co-inhibitors of acyl-CoA: cholesterol-acyl transferase, based on N,N′,N′-trisubstituted 5-bis-aminomethylene-1,3-dioxane-4,6-dione, are also shown in the patent ES2077985 with the formula:
